Salehi Sepehr, Wang Xiaomin, Juvet Stephen, Scott Jeremy A, Chow Chung-Wai
Division of Respirology, Department of Medicine, Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada.
Division of Medical Sciences, Northern Ontario School of Medicine, Thunder Bay, Ontario, Canada.
PLoS One. 2017 Jan 20;12(1):e0163614. doi: 10.1371/journal.pone.0163614. eCollection 2017.
Asthma is a chronic inflammatory disease characterized by airways hyper-responsiveness (AHR), reversible airway obstruction, and airway inflammation and remodeling. We previously showed that Syk modulates methacholine-induced airways contractility in naïve mice and in mice with allergic airways inflammation. We hypothesize that Syk plays a role in the pathogenesis of AHR; this was evaluated in a chronic 8-week mouse model of house dust mite (HDM)-induced allergic airways inflammation.
We used the Sykflox/flox//rosa26CreERT2 conditional Syk knock-out mice to assess the role of Syk prior to HDM exposure, and treated HDM-sensitized mice with the Syk inhibitor, GSK143, to evaluate its role in established allergic airways inflammation. Respiratory mechanics and methacholine (MCh)-responsiveness were assessed using the flexiVent® system. Lungs underwent bronchoalveolar lavage to isolate inflammatory cells or were frozen for determination of gene expression in tissues.
MCh-induced AHR was observed following HDM sensitization in the Syk-intact (Sykflox/flox) and vehicle-treated BALB/c mice. MCh responsiveness was reduced to control levels in HDM-sensitized Sykdel/del mice and in BALB/c and Sykflox/flox mice treated with GSK143. Both Sykdel/del and GSK143-treated mice mounted appropriate immune responses to HDM, with HDM-specific IgE levels that were comparable to Sykflox/flox and vehicle-treated BALB/c mice. HDM-induced increases in bronchoalveolar lavage cell counts were attenuated in both Sykdel/del and GSK143-treated mice, due primarily to decreased neutrophil recruitment. Gene expression analysis of lung tissues revealed that HDM-induced expression of IL-17 and CXCL-1 was significantly attenuated in both Sykdel/del and GSK143-treated mice.
Syk inhibitors may play a role in the management of neutrophilic asthma.
哮喘是一种慢性炎症性疾病，其特征为气道高反应性（AHR）、可逆性气道阻塞以及气道炎症和重塑。我们之前表明，脾酪氨酸激酶（Syk）可调节未致敏小鼠和过敏性气道炎症小鼠中乙酰甲胆碱诱导的气道收缩性。我们假设Syk在AHR的发病机制中起作用；这在屋尘螨（HDM）诱导的过敏性气道炎症的慢性8周小鼠模型中进行了评估。
我们使用Sykflox/flox//rosa26CreERT2条件性Syk基因敲除小鼠，在HDM暴露前评估Syk的作用，并使用Syk抑制剂GSK143处理HDM致敏的小鼠，以评估其在已建立的过敏性气道炎症中的作用。使用flexiVent®系统评估呼吸力学和乙酰甲胆碱（MCh）反应性。对肺进行支气管肺泡灌洗以分离炎性细胞，或将肺冷冻以测定组织中的基因表达。
在Syk完整（Sykflox/flox）和载体处理的BALB/c小鼠中，HDM致敏后观察到MCh诱导的AHR。在HDM致敏的Sykdel/del小鼠以及用GSK143处理的BALB/c和Sykflox/flox小鼠中，MCh反应性降低至对照水平。Sykdel/del小鼠和GSK143处理的小鼠对HDM均产生了适当的免疫反应，HDM特异性IgE水平与Sykflox/flox和载体处理的BALB/c小鼠相当。在Sykdel/del小鼠和GSK143处理的小鼠中，HDM诱导的支气管肺泡灌洗细胞计数增加均减弱，主要是由于中性粒细胞募集减少。肺组织的基因表达分析显示，在Sykdel/del小鼠和GSK143处理的小鼠中，HDM诱导的IL-17和CXCL-1表达均显著减弱。
Syk抑制剂可能在嗜中性粒细胞性哮喘的治疗中起作用。
